title: Activation of the MAS receptor by angiotensin-(1-7) in the renin-angiotensin system mediates mesenteric vasodilatation in cirrhosis.
abstract: OBJECTIVE
  Splanchnic vascular hypocontractility with subsequent increased portal venous inflow leads to portal hypertension. Although the renin-angiotensin system contributes to fibrogenesis and increased hepatic resistance in patients with cirrhosis, little is known about its effects in the splanchnic vasculature, particularly those of the alternate system in which angiotensin (Ang) II is cleaved by the Ang-converting enzyme-2 (ACE2) to Ang-(1-7), which activates the G-protein-coupled Mas receptor (MasR). We investigated whether this system contributes to splanchnic vasodilatation and portal hypertension in cirrhosis.
  
  
  METHODS
  We measured levels of renin-angiotensin system messenger RNA and proteins in splanchnic vessels from patients and rats with cirrhosis. Production of Ang-(1-7) and splanchnic vascular reactivity to Ang-(1-7) was measured in perfused mesenteric vascular beds from rats after bile-duct ligation. Ang-(1-7) and MasR were blocked in rats with cirrhosis to examine splanchnic vascular hemodynamics and portal pressure response.
  
  
  RESULTS
  Levels of ACE2 and MasR were increased in splanchnic vessels from cirrhotic patients and rats compared with healthy controls. We also observed an ACE2-dependent increase in Ang-(1-7) production. Ang-(1-7) mediated splanchnic vascular hypocontractility in ex vivo splanchnic vessels from rats with cirrhosis (but not control rats) via MasR stimulation. Identical effects were observed in the splanchnic circulation in vivo. MasR blockade reduced portal pressure, indicating that activation of this receptor in splanchnic vasculature promotes portal inflow to contribute to development of portal hypertension. In addition, the splanchnic effects of MasR required nitric oxide. Interestingly, Ang-(1-7) also decreased hepatic resistance.
  
  
  CONCLUSIONS
  In the splanchnic vessels of patients and rats with cirrhosis, increased levels of ACE2 appear to increase production of Ang-(1-7), which leads to activation of MasR and splanchnic vasodilatation in rats. This mechanism could cause vascular hypocontractility in patients with cirrhosis, and might be a therapeutic target for portal hypertension.
authors.affiliation: Department of Medicine, The University of Melbourne, Heidelberg Repatriation Hospital, Heidelberg, Melbourne, Victoria, Australia; Austin Health, Austin Hospital, Heidelberg, Melbourne, Victoria, Australia.
authors.forename: Josephine A
authors.initials: JA
authors.lastname: Grace
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.forename: Chandana B
authors.initials: CB
authors.lastname: Herath
authors.forename: Michaela
authors.initials: M
authors.lastname: Granzow
authors.forename: Robert
authors.initials: R
authors.lastname: Schierwagen
authors.forename: Noemi
authors.initials: N
authors.lastname: Masing
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Louise M
authors.initials: LM
authors.lastname: Burrell
authors.forename: Peter W
authors.initials: PW
authors.lastname: Angus
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000503:physiopathology*; D008638:Mesenteric Arteries / Q000503:physiopathology*; D009569:Nitric Oxide / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000502:physiology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects*; D014655:Vascular Resistance; D014664:Vasodilation / Q000502:physiology*
chemical_list: C000715470:MAS1 protein, human; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D009569:Nitric Oxide; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)
keywords: ACE; AT1R; AT2R; Ang; BDL; CCl(4); HVR; Hemodynamics; Mas receptor; MasR; NOS; PP; Portal Hypertension; RAS; Rat Model; SpVR; VASP; angiotensin; angiotensin II type 1 receptor; angiotensin II type 2 receptor; angiotensin-converting enzyme; bile duct ligation; carbon tetrachloride; eNOS; endothelial nitric oxide synthase; hepatic vascular resistance; iNOS; inducible nitric oxide synthase; nitric oxide synthase; portal pressure; renin−angiotensin system; splanchnic vascular resistance; vasodilator-stimulated phosphoprotein